Post on 25-Oct-2014
DRUGS ACTING ON GIT
Antiemetics
&
Prokinetics
Dr. Basant K. Mohanty
Unit of Pharmacology
UniKL RCMP
Objectives
To know the mechanism of vomiting including neurotransmitters involved
To classify the various drugs that are used as antiemetics
To know the mechanism of action, specific uses and common side effects of commonly used antiemetics and their use in specific conditions
To know the mechanism of action, therapeutic uses and adverse effects of prokinetics
To know the common emetics used in clinical practice and contraindications to their use
Nausea - A feeling of impending vomiting
Vomiting – Forceful expulsion of gastric contents through
the mouth.
Nausea & Vomiting are protective reflexes and the major
physiological function of emesis (vomiting) is to remove
toxic or harmful substances from the body.
Vomiting occursVomiting occurs in gastroenteritis, motion sickness, in gastroenteritis, motion sickness,
surgery, pregnancy, poisoning, radiation & as an ADR of surgery, pregnancy, poisoning, radiation & as an ADR of
several drugs mostly drugs used for cancer several drugs mostly drugs used for cancer
chemotherapy.chemotherapy.
Central Neural Regulation of vomiting
Central Neural Regulation of vomiting:
Vomiting centre coordinates motor mechanisms of vomiting. Receives impulses from:
Chemoreceptor trigger zone (CTZ)
Higher cortical centres
Peripheral tissues (GIT)
Vestibular apparatus (motion sickness)
CTZ is stimulated by drugs and by chemicals & toxins produced in uremia, infections etc.
Antiemetics act by blocking either histamine & or serotonin & or dopamine & or cholinergic receptors.
Opioids
Chemothe.
Anaesthecia
Chemothe.
Radiothe.
Motion sickness
Neurologic pathways involved in Neurologic pathways involved in nausea & vomitingnausea & vomiting
Class Drug
5-HT3 – R antagonists Ondansetron, Granisetron
Dopamine antagonists Metoclopramide, Domperidone
Antimuscarinics Scopolamine (l-hyoscine)
Anti-histamines Cyclizine, Promethazine, Doxylamine
Cannabinoids Nabilone, Dronabinol
Antacids Magnesium hydroxide, aluminium hydroxide either alone or in combination
H2 receptor antagonis Ranitinidine, famotidine etc.
Miscellaneous Dexamethasone, Diazepam, antipsychotic (droperidol)
Classification of Anti-emetic drugs
Site of action of Antiemetics
H1, M1, DA2 antagonists Nabilone
Benzodiazepines
5HT anta.
Prokinetic agents
Motion sickness
Hyoscine
Antihistamines
H1, M1, DA2 antagonists, Nabilone
Benzodiazepines
5HT anta.
Prokinetic agents
Mechanism of action of 5-HT3 antagonists
5 HT3 antagonists Ondansetron & Granisetron
Mechanism: Block serotonergic (5-HT3) receptors
in the centre & periphery - gut.
ADR: well tolerated but can cause headache,
constipation & in some patients QT prolongation.
Route: Oral, IV (slow injection or infusion)
Uses: For prevention & treatment of vomiting due
to anticancer agents, radiation & postoperative
vomiting.
Status: Most effective antiemetic in anticancer
agent induced vomiting.
Corticosteroids & diazepam enhance its activity.
Metoclopramide & DomperidoneMetoclopramide & Domperidone
Mechanism:
Block DA2 receptors in CTZ
Cholinomimetic action - GI motility Rapid transit of
food through the upper GI tract
Route: Oral, im, iv
ADR: Hyperprolactinemia, Extra pyramidal syndrome
(EPS) only with metoclopramide. (Domperidone does
not cross BBB & hence, no EPS)
Mechanism of action of metoclopramide and domperidone
Metoclopramide & Domperidone ..
Uses:
Anti-emetics (not for motion sickness)
Gastro-esophageal reflux disorder (GERD)
by prokinetic action they hasten gastric
emptying & prevent aspiration of gastric contents
into lungs. Hence, used in the preoperative
preparation of patients for emergency general
anaesthecia.
Hyoscine (scopolamine)
Mechanism: Block muscarinic (M1) R
in vestibular apparatus
ADR: drowsiness, dryness of mouth,
blurred vision & other atropine like
side effects
Uses: for prevention and treatment
of motion sickness, sea sickness
etc.
Hyoscine transdermal patch placed
behind the ear works for 3 days.
Antihistamines – Cyclizine, promethazine etc.
Block H1 & M1 (atropine like action) receptors.
ADR & uses similar to hyoscine
Nabilone & Dronabinol: Synthetic cannabinoids
Mechanism: prevents stimulation of CTZ
ADR: Mood changes, drowsiness, psychotic reactions,&
drug dependence
Uses: Reserved drug for anticancer drug induced
vomiting and radiation sickness
Antacids: Magnesium hydroxide &/or aluminium hydroxide
Mechanism: from first to last gastric acid neutralization
Uses: 15 to 30ml doses of single or multiple agents may
provide relief from simple nausea and vomiting associated
with heart burn and gastroesophageal reflux Histamine ( H2 ) receptor antagonists:
Ranitidine, famotidine etc. May be used in low doses to manage simple nausea and vomiting associated with heartburn or gastroesophageal reflux.
Corticosteroids: Dexamethasone.
Mechanism – not known.
May inhibit prostaglandin synthesis.
Uses: synergistic with other antiemetics in anticancer
drug induced vomiting
Diazepam, Lorazepam: May control anticipatory
vomiting by sedative & antianxiety action.
Uses: synergistic with other antiemetics in anticancer
drug induced vomiting
Treatment of vomitingMotion sickness – is caused by stimulation of vestibular apparatus. As prevention is better, the drug is to be taken 1 hour before the journey – Hyoscine, Cyclizine
Anticancer agents induced vomiting – 5-HT plays a major role.
Ondansetron, Metoclopramide, Corticosteroids
Postoperative vomiting & vomiting due to other causes – Metoclopramide, Ondansetron
Vomiting in pregnancy – Reassurance. Pyridoxine alone or Promethazine + Pyridoxine or pyridoxine + doxylamine only if absolutely necessary
Vomiting in children- pediatric gastroenteritis - pediatric gastroenteritis - rehydration rehydration
measures. Children receiving chemotherapy a measures. Children receiving chemotherapy a corticosteroidcorticosteroid plus plus
5-HT 5-HT 33 receptor receptor antagonist may be preferred.antagonist may be preferred.
Prokinetic agents
The drugs that enhance the coordinated activity among various segments of the gut to propel the luminal contents.Drugs that increase lower esophageal sphincter pressure (hence useful for GERD);drugs that speed up gastric emptying (hence used for gastroparesis);agents that stimulate small intestine (hence useful for postoperative paralytic ileus and colonic pseudo-obstruction;and finally agents that enhance colonic transit (hence useful for treatment of constipation)
Prokinetic agents cont…..Prokinetic agents cont…..
Metoclopramide, Domperidone – in addition to being
antiemetics, they are also prokinetic agents.
Cisapride, mosapride and renzapride – 5HT 4 agonists
They are prokinetic agents and enhance the action of
acetylcholine on upper GIT, having no antiemetic
actions and used for GERD, non-ulcer dyspepsia,
impaired gastric emptying and constipation
Cisapride is no longer used due to it’s serious adverse
effects like prolongation of QT interval and ventricular
arrhythmia
Miscellaneous Prokinetic agents Miscellaneous Prokinetic agents
Levosulpiride – A newer D2 receptor antagonist
which is being developed
Tegaserod and prukalopride – Recent additions of
5HT4 agonists and safe and exhibit full prokinetic
effects and useful for constipation dominant
irritable bowel syndrome
Loxiglumide – A CCK1 receptor antagonist
recently developed to improve and speed up
gastric emptying and GI motility
Effects of metoclopramide and domperidone
EmeticsEmetics
The drugs that produce vomitingThe drugs that produce vomiting
Mustard and common salt – Peripherally acting by irritation of Mustard and common salt – Peripherally acting by irritation of
stomach and used as household emeticsstomach and used as household emetics
Morphine & apomorphine – centrally acting by stimulating CTZMorphine & apomorphine – centrally acting by stimulating CTZ
Syrup epecac - acts both centrally and peripherally & safe Syrup epecac - acts both centrally and peripherally & safe
emeticemetic
Emetics are indicated in certain cases of poisoningEmetics are indicated in certain cases of poisoning
Contraindications of use of emetics
Hypertension, peptic ulcer, pulmonary tuberculosis,
uremia, and pregnancy
Corrosive poisoning because increase in
intragastric pressure may lead to perforation
Poisoning due to petroleum products because of
danger of producing lipoid aspiration pneumonia
Lecture outcomesAt the end of the lecture the student should be able
describe:
The mechanism of vomiting
The various drugs that are used as antiemetics with their mechanism of action, specific uses and adverse effects
The meaning of prokinetics and the various drugs used as prokinetics in clinical practice with their mechanism of action, specific uses and adverse effects
Common emetics used for poisoning and the contraindications to their use
Thank you
Sites of action of Antiemetics
H1, M1, DA2 antagonists Nabilone
Benzodiazepines
5HT anta.
Prokinetic agents
Motion sickness
A Benzodiazepines
Prokinetic agents
A A
B
C
D